Targeting intrinsically disordered proteins at the edge of chaos

Hao Ruan; Qi Sun; Weilin Zhang; Ying Liu; Luhua Lai

doi:10.1016/j.drudis.2018.09.017

Targeting intrinsically disordered proteins at the edge of chaos

Drug Discov Today. 2019 Jan;24(1):217-227. doi: 10.1016/j.drudis.2018.09.017. Epub 2018 Sep 29.

Authors

Hao Ruan¹, Qi Sun¹, Weilin Zhang¹, Ying Liu², Luhua Lai³

Affiliations

¹ BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
² BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Center for Quantitative Biology, Peking University, Beijing 100871, China.
³ BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Center for Quantitative Biology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: [email protected].

PMID: 30278223
DOI: 10.1016/j.drudis.2018.09.017

Abstract

Intrinsically disordered proteins or intrinsically disordered regions (IDPs or IDRs) are those that do not fold into defined tertiary structures under physiological conditions. Given their prevalence in various diseases, IDPs are attractive therapeutic targets. However, because of the dynamic nature of the IDP structure, conventional structure-based drug design methods cannot be directly applied. Thanks to recent progress in understanding the mechanisms underlying IDP and ligand interactions, computational strategies for IDP-targeted rational drug discovery are emerging. Here, we summarize recent developments in computational IDP drug design strategies and their successful applications, analyze the typical properties of reported IDP-binding compounds (iIDPs), and discuss the major challenges ahead as well as possible solutions.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Drug Design
Drug Discovery
Humans
Intrinsically Disordered Proteins / metabolism*
Ligands

Substances

Intrinsically Disordered Proteins
Ligands